Antecedents and Consequences of Cocaine Taking: Impact of Oxytocin

吸食可卡因的前因和后果：催产素的影响

• 批准号: 10408141
• 负责人: Suzette M Evans
• 金额: $ 62.02万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408141
• 关键词: Accounting; Acute; Affect; Aggressive behavior; Amphetamines; Animals; Behavior; Behavioral; Cocaine; Corpus striatum structure; Data; Data Set; Desire for food; Development; Dopamine; Drug usage; Estrogens; Female; Food; Grooming; Hippocampus (Brain); Intake; Intravenous; Luteal Phase; Macaca fascicularis; Macaca mulatta; Measures; Mediating; Menstrual cycle; Monkeys; Oxytocin; Palate; Peripheral; Pharmaceutical Preparations; Physiology; Primates; Progesterone; Prospective Studies; Rattus; Research; Risk Factors; Running; Same-sex; Self Administration; Sex Differences; Social Behavior; Social status; Standardization; Structure; System; Testing; antagonist; base; behavioral response; cocaine self-administration; cohort; diketopiperazine; drug of abuse; indexing; male; neurogenesis; nonhuman primate; peptide hormone; proliferative phase Menstrual cycle; prospective; reinforcer; relating to nervous system; response; sex; social; social attachment; social structure; standard measure; trait

Dominance behaviors and social status in primates affects physiology, neural structure, behavior and response to drugs of abuse. Oxytocin (OXT), a peptide hormone associated with dominance behavior modulates cocaine self-administration and is associated with hippocampal (HC) volume. Male dominance commonly relies on aggression while female dominance commonly relies on grooming. We hypothesize that the different behaviors associated with male and female social structure account for the sex differences in cocaine self-administration observed in socially-housed cynomolgus monkeys. Thus, both dominance behavior and sex moderate drug response, yet studies on the interaction of these two variables are sorely missing. We hypothesize that dominance behavior is a significant factor accounting for biologically relevant variability in research with non- human primates. Therefore, we propose a prospective study on the effects of sex, menstrual cycle, dominance behavior and cocaine self-administration on OXT levels and HC volume in rhesus monkeys and the effects of manipulating OXT on cocaine self-administration. We will use standardized, same-sex dyad-interaction tests to obtain a dominance-index for each monkey. Our preliminary data show that the dominance-index, even in singly-housed non-human primates, is related to striatal dopamine release, the reinforcing effects of cocaine, the appetitive effects of amphetamine, and HC volume. Thus the dominance-index is a relevant measure of a behavioral trait related to both social and non-social reinforcers. Aim 1. Determine the effect of dominance- index on HC volume and OXT levels in male (n = 10) and female (n = 10) rhesus monkeys. Aim 2a. Determine the reinforcing effects of self-administered i.v. cocaine and palatable food as a function of dominance-index. Aim 2b. Determine the effects of menstrual cycle and dominance-index on the reinforcing effects of self- administered i.v. cocaine and palatable food. Aim 3. Determine the effects of (9 mo) cocaine self- administration on HC volume and OXT levels as a function of the dominance-index. Aim 4. Determine the effects of a) increasing OXT levels by acute administration of SOC1, developed by Iain MacGregor, b) decreasing OXT effects by acute administration of the OXT antagonist 2,5- diketopiperazine (DTP) and c) SOC1 + DTP on cocaine self-administration as a function of the dominance-index. Impact. We will dynamically and prospectively track HC volume and OXT levels in male and female rhesus monkeys in order to assess the extent to which these measures are risk factors for drug use, consequences of drug use, or both. By using naturally varying dominance-indexes, we will be able to tease out the effects of environmental conditions from cocaine taking. This proposal will provide an empirical basis for the development of biologically-informed manipulations of the oxytocin system, and behaviorally-informed treatments based on social behavior for both males and females.

灵长类动物的优势行为和社会地位影响生理、神经结构、行为和反应 滥用药物。催产素 (OXT) 是一种与支配行为相关的肽激素，可调节可卡因 自我给药并与海马 (HC) 体积相关。男性的统治地位通常依赖于 攻击性，而女性的主导地位通常依赖于修饰。我们假设不同的行为 与男性和女性社会结构相关的可卡因自我给药的性别差异 在社会饲养的食蟹猴中观察到。因此，支配行为和性别都会调节药物 反应，但对这两个变量相互作用的研究却非常缺失。我们假设 优势行为是解释非非研究中生物学相关变异的一个重要因素。 人类灵长类动物。因此，我们提出一项关于性别、月经周期、主导地位的影响的前瞻性研究。 行为和可卡因自我给药对恒河猴 OXT 水平和 HC 体积的影响以及 操纵 OXT 进行可卡因自我给药。我们将使用标准化的同性二元互动测试来 获得每只猴子的优势指数。我们的初步数据表明，即使在 单居非人类灵长类动物，与纹状体多巴胺释放、可卡因的增强作用有关， 安非他明的食欲影响和 HC 量。因此，优势指数是衡量 与社会和非社会强化物相关的行为特征。目标 1. 确定支配地位的影响—— 雄性 (n = 10) 和雌性 (n = 10) 恒河猴 HC 体积和 OXT 水平的指数。目标 2a。决定 自我注射静脉注射的强化作用可卡因和美味食物作为优势指数的函数。 目标 2b。确定月经周期和优势指数对自我强化效果的影响 静脉注射可卡因和美味的食物。目标 3. 确定（9 个月）可卡因自我作用的效果 HC 体积和 OXT 水平的管理作为优势指数的函数。目标 4. 确定 a) 通过急性施用 SOC1（由 Iain MacGregor 开发）增加 OXT 水平的影响，b) 通过急性施用 OXT 拮抗剂 2,5-二酮哌嗪 (DTP) 来降低 OXT 效应和 c) SOC1 + DTP 对可卡因自我给药的影响，作为优势指数的函数。 影响。我们将动态、前瞻性地追踪雄性和雌性恒河猴的 HC 体积和 OXT 水平 猴子，以评估这些措施在多大程度上是吸毒的危险因素、吸毒的后果 吸毒，或两者兼而有之。通过使用自然变化的优势指数，我们将能够梳理出 吸食可卡因造成的环境条件。该建议将为以下方面提供经验基础： 催产素系统的生物学操纵和行为操纵的发展 基于男性和女性社会行为的治疗。